Targeted drug delivery is of critical importance in ensuring safety and efficacy of therapeutic and diagnostic agents. In cancer treatment and diagnosis, for example, targeted delivery directly to the tumor site allows more effective dosing at the tumor sites than systemic delivery, therefore increasing drug effectiveness while reducing side effects. Diagnostic or therapeutic agents conjugated to targeting moieties such as antibodies or antibody fragments, cell- or tissue-specific peptides, hormones and other receptor binding molecules have previously been studied. (See, e.g., U.S. Pat. Nos. 3,927,193, 4,331,647, 4,348,376, 4,361,544, 4,468,457, 4,444,744, 4,460,459, 4,460,561, 4,624,846 and 4,818,709).
A significant challenge for direct targeting methods, such as through antibody vectors, is that a relatively small fraction of the conjugate actually binds to the target site, while the majority of the antibody conjugate molecules remain in circulation. Such antibody-agent conjugate molecules often negatively affect the functionality of the active agent and cause undesirable marrow toxicity or other systemic side effects. Besides limiting dosing, the circulating antibody-agent conjugate molecules also increase background noise and reduce resolution in a diagnostic application. In islet imaging, because islets constitute only 1-2% of the pancreatic mass, additional difficulty appears within the organ and highly specific delivery is more crucial. (See, e.g., Liu, et al. 2011 Mol. Pharmaceutics 8, 767-773; Liu, et al. 2012 Nuclear Medicine and Biology 39, 645-651.)
To increase the target to background ratios, pretargeting methods and clearing agents have been studied. An example of pretargeting method is a (strept)avidin-biotin system. Another example is the use of the bispecific antibody-hapten recognition system, which uses a radiolabeled hapten and a bispecific antibody in place of (strept)avidin and biotin. (See, e.g., Barbet, et al. 1999 Cancer Biother. Radiopharm. 14:153-166; Karacay, et al. 2000 Bioconj. Chem. 11: 842-854; Gautherot, et al. 2000 J. Nucl. Med. 41:480-487; Lubic, et al. 2001 J. Nucl. Med. 42:670-678; Gestin, et al. 2001 J. Nucl. Med. 42:146-153.) However, the affinity of an antibody for its hapten, particularly for a monovalent one, is orders of magnitude lower than that of (strept)avidin for biotin.
Existing targeting and clearance systems, however, suffer from low clearance efficiency as well as nonspecific background, which remain as major hurdles to creating an effective targeted delivery system. A novel pretargeting approach is especially desired that has enhanced clearing effectiveness and reduced non-specific background.